Method for the synthesis of s-indoline-2-carboxylic acid and application thereof in the synthesis of perindopril

ABSTRACT

Process for the synthesis of (2S)-indoline-2-carboxylic acid of formula (I): 
     
       
         
         
             
             
         
       
     
     Application in the synthesis of perindopril and its pharmaceutically acceptable salts.

The present invention relates to a process for the synthesis of(2S)-indoline-2-carboxylic acid, and to its application in the synthesisof perindopril and pharmaceutically acceptable salts thereof.

More specifically, the present invention relates to a new process forthe industrial synthesis of (2S)-indoline-2-carboxylic acid of formula(I):

The compound of formula (I) obtained according to the process of theinvention is useful in the synthesis of perindopril of formula (II):

and in the synthesis of pharmaceutically acceptable salts thereof.

Perindopril and salts thereof have valuable pharmacological properties.

Their principal property is that of inhibiting angiotensin I convertingenzyme (or kininase II), which allows, on the one hand, prevention ofthe conversion of the decapeptide angiotensin I to the octapeptideangiotensin II (a vasoconstrictor) and, on the other hand, prevention ofthe degradation of bradykinin (a vasodilator) to an inactive peptide.

Those two actions contribute to the beneficial effects of perindopril incardiovascular diseases, more especially in arterial hypertension andheart failure.

Perindopril, its preparation and its use in therapeutics have beendescribed in the European patent specification EP 0 049 658.

In view of the pharmaceutical value of this compound, it has beenimportant to be able to obtain the intermediate of formula (I) by aneffective synthesis process that allows the (S) enantiomer to beobtained selectively in a very good yield and with excellent purity.

Some methods for the preparation of the compound of formula (I) arealready known.

Thus, the patent specifications EP 0 308 339 and EP 0 308 341 describeobtaining (2S)-indoline-2-carboxylic acid by resolution of racemicindoline-2-carboxylic acid using (R)-α-methylbenzylamine. The(R)-α-methylbenzylamine salt of (2S)-indoline-2-carboxylic acid isisolated by fractional crystallisation, then acidified to yield thecompound of formula (I).

That method has the advantage of using a starting material and reagentsthat are reasonably priced and very readily accessible.

On the other hand, the yield of the compound of formula (I) using thatmethod is only 35%.

The Applicant has now developed a process for the synthesis of thecompound of formula (I) in which the (2R) isomer, which is formed duringthe course of the resolution reaction, is recycled. The processdeveloped in that way makes it possible to obtain the compound offormula (I) in a yield, starting from racemic indoline-2-carboxylicacid, that ranges from 50% to 70%, according to the number of recyclingoperations carried out.

More specifically, the present invention relates to a process for thesynthesis of the compound of formula (I) which is characterised in thatracemic indoline-2-carboxylic acid of formula (III):

-   -   is reacted with a chiral amine    -   to yield the salt of formula (IV):

-   -   which is filtered off, and there being isolated:        -   on the one hand the (2S) isomer of formula (IV a):

-   -   -   -   in the form of crystals,            -   which compound of formula (IV a) is then treated with                hydrochloric acid to yield the compound of formula (I),

        -   and on the other hand a mixture of the (2S) isomer of            formula (IV a) and the (2R) isomer of formula (IV b) in            which the (2R) isomer predominates:

-   -   -   -   by evaporation of the filtrate,            -   which mixture is then treated with hydrochloric acid to                yield a mixture of (2R)-indoline-2-carboxylic acid and                (2S)-indoline-2-carboxylic acid in which the (2R) acid                predominates,            -   which is racemised by reaction with sodium hydroxide                solution,            -   at a temperature of from 140 to 200° C.,            -   under a pressure of from 5 to 15 bars,            -   to yield, after isolation, the compound of formula                (III), with which the series of operations described                above is repeated,                then, after having carried out from 2 to 6 cycles, all                the portions made up of the compound of formula (I) are                combined.

The compound of formula (I) is thereby obtained in a yield ranging from50% to 70%, according to the number of cycles carried out.

Its chemical and enantiomeric purity is very good, which makes its usein the synthesis of perindopril of formula (II) especially advantageous.

By way of illustration, the catalytic hydrogenation of the compound offormula (I) obtained according to the process of the invention, followedby coupling of the (2S,3aS,7aS)-perhydroindole-2-carboxylic acid soobtained with the compound of formula (VI):

allows perindopril of formula (II) to be obtained in very satisfactorypurity and yield.

The present invention relates also to a variant of the above process inwhich there is reacted (2R)-indoline-2-carboxylic acid of formula (V):

-   -   which is racemised by reaction with sodium hydroxide solution,    -   at a temperature of from 140 to 200° C.,    -   under a pressure of from 5 to 15 bars,    -   to yield, after isolation, the compound of formula (III):

-   -   which is reacted with a chiral amine    -   to yield the salt of formula (IV):

-   -   which is filtered off, and there being isolated:        -   on the one hand the (2S) isomer of formula (IV a):

-   -   -   -   in the form of crystals,            -   which compound of formula (IV a) is then treated with                hydrochloric acid to yield the compound of formula (I),

        -   and on the other hand a mixture of the (2S) isomer of            formula (IV a) and the (2R) isomer of formula (IV b) in            which the (2R) isomer predominates:

-   -   -   -   by evaporation of the filtrate,            -   which mixture is then treated with hydrochloric acid to                yield a mixture of (2R)-indoline-2-carboxylic acid and                (2S)-indoline-2-carboxylic acid in which the (2R) acid                predominates,            -   with which there is repeated, if desired, the series of                operations described above,

    -   then, after having carried out from 1 to 6 cycles, all the        portions made up of the compound of formula (1) are combined.

Among the chiral amines that can be used in the process according to theinvention or its variant there may be mentioned, without implying anylimitation, (R)-α-methylbenzyl-amine, 1-(1-naphthyl)-ethylamine,ephedrine, α-chymotrypsin, sec-butylamine, 1-amino-2-methylbutane,N,N-dimethyl-1-phenylethylamine, 1-cyclohexylethylamine, cycloserine,2-(methoxymethyl)-pyrrolidine, α-dimethylamino-ε-caprolactam,isobornylamine, 1-(4-nitrophenyl)-ethylamine, α-amino-ε-caprolactam,2-amino-1-butanol, 1-amino-2-propanol, cinchonidine, cinchonine,N-methyl-ephedrine, phenylalaninol, quinidine, valinol,α-phenyl-glycinol, leucinol.

The preferred chiral amine is (R)-α-methylbenzylamine.

“Mixture in which (2R) predominates” is understood to mean a mixture of(2R) and (2S) isomers in which the (2R) isomer forms the majority of themixture.

The Example below illustrates the invention.

EXAMPLE (2S)-indoline-2-carboylic acid

Step A: Resolution of Racemic indoline-2-carboxylic acid

3.7 kg of (R)-α-methylbenzylamine are added to a solution of 5 kg ofindoline-2-carboxylic acid in ethanol and then the mixture is stirredfor 2 h and filtered.

Step A₁: (2S)-indoline-2-carboxylic acid

The white precipitate collected in Step A is recrystallised fromisopropanol and then dissolved in 13 liters of water, and 12 liters of a1N hydrochloric acid solution are added. After stirring for 2 h, theprecipitate is filtered off and then washed and dried to yield(2S)-indoline-2-carboxylic acid (<<1^(st) portion>>) in the form ofcrystals (1.80 kg) with a chemical purity of 98% and an enantiomericpurity greater than 99.5%.

Step A₂: Idoline-2-carboxylic acid (Mixture in Which (2R) Predominates)

The filtrate collected in Step A is evaporated and the residue obtainedis dissolved in 13 liters of water and then 12 liters of a 1 Nhydrochloric acid solution are added. After stirring for 2 h, theprecipitate is filtered off and then washed and dried to yieldindoline-2-carboxylic acid in the form of a mixture of the (2R) and (2S)enantiomers (2.6 kg) in which the (2R) enantiomer predominates.

Step B: Racemisation

Introduce into an autoclave the precipitate obtained in Step A₂ (2.6kg), and then 12 liters of water and 3.1 liters of an 8.65N sodiumhydroxide solution, then heat at 170° C. for 3 h under a pressure of 7bars.

The reaction mixture is subsequently brought to ambient temperature andthen transferred to a reactor, and concentrated hydrochloric acid issubsequently added until a pH of 3.4 is reached while maintaining thetemperature between 20 and 25° C.

The mixture is then stirred for 1 h and the precipitate is subsequentlyfiltered off, washed and dried to yield racemic indoline-2-carboxylicacid in a yield of 90% (2.34 kg).

Step C: Recycling of indoline-2-carboxylic Acid

The racemic indoline-2-carboxylic acid obtained in Step B (2.34 kg) isresolved according to the procedure in Step A.

The (R)-α-methylbenzylamine salt of (2S)-indoline-2-carboxylic acid soformed is isolated and then treated with hydrochloric acid according tothe procedure in Step A₁ to yield (2S)-indoline-2-carboxylic acid(<<2^(nd) portion>>) in the form of crystals (0.84 kg) having a chemicalpurity of 98% and an enantiomeric purity greater than 99.5%.

The 1^(st) portion, obtained in Step A₁, and the 2^(nd) portion,obtained in Step C, are then combined.

(2S)-indoline-2-carboxylic acid is thereby obtained in a total yield of52.8%, a chemical purity of 98% and an enantiomeric purity greater than99.5%.

1. A process for the synthesis of (2S)-indoline-2-carboxylic acid offormula (I):

wherein a racemic indoline-2-carboxylic acid of formula (III):

is reacted with a chiral amine to yield a salt of formula (IV):

which is filtered off, to yield: the (2S) isomer of formula (IV a):

in the form of crystals, which compound of formula (IV a) is treatedwith hydrochloric acid to yield the compound of formula (I), and afterevaporation of the filtrate, a mixture of the (2S) isomer of formula (IVa) and the (2R) isomer of formula (IV b) in which the (2R) isomerpredominates:

which mixture is treated with hydrochloric acid to yield a mixture of(2R)-indoline-2-carboxylic acid and (2S)-indoline-2-carboxylic acid inwhich the (2R) acid predominates, the mixture is racemized by reactionwith a sodium hydroxide solution, at a temperature of from 140 to 200°C., under a pressure of from 5 to 15 bars, to yield, after isolation,the compound of formula (III), which is then re-subjected to the seriesof operations described above, after having carried out between 2 and 6cycles of the above-described series of operations, all the portionsmade up of the compound of formula (I) are combined.
 2. A process forthe synthesis of (2S)-indoline-2-carboxylic acid of formula (I):

wherein (2R)-indoline-2-carboxylic acid of formula (V):

is racemized by reaction with a sodium hydroxide solution, at atemperature of from 140 to 200° C., under a pressure of from 5 to 15bars, to yield, after isolation, a compound of formula (III):

which is reacted with a chiral amine, to yield a salt of formula (IV):

which is filtered off, to yield: the (2S) isomer of formula (IV a):

in the form of crystals, which compound of formula (IV a) is treatedwith hydrochloric acid to yield the compound of formula (I), and, afterevaporation of the filtrate, a mixture of the (2S) isomer of formula (IVa) and the (2R) isomer of formula (IV b) in which the (2R) isomerpredominates:

which mixture is treated with hydrochloric acid to yield a mixture of(2R)-indoline-2-carboxylic acid and (2S)-indoline-2-carboxylic acid inwhich the (2R) acid predominates, the mixture is re-subjected, ifdesired, to the series of operations described above, after havingcarried out from 1 to 6 cycles of the above-described series ofoperations, all the portions made up of the compound of formula (I) arecombined.
 3. A process according to claim 1, wherein the chiral amine is(R)-α-methylbenzylamine.
 4. A process according to claim 2, wherein thechiral amine is (R)-α-methylbenzylamine.